Tetracyclic steroid derivatives useful as progesterone receptor modulators

ABSTRACT

The present invention is directed to tetracyclic steroid derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by a progesterone or glucocorticoid receptor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application60/774,348, filed on Feb. 17, 2006, which is incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The present invention is directed to tetracyclic steroid derivatives,pharmaceutical compositions containing them and their use in thetreatment of disorders and conditions modulated by a progesterone orglucocorticoid receptor. More particularly, the compounds of the presentinvention are useful in the treatment of disorders including, but notlimited to, secondary amenorrhea; dysfunctional bleeding; uterineleiomyomata; endometriosis; polycystic ovary syndrome; carcinomas andadenocarcinomas of the endometrium, ovary, breast, colon and/orprostate, Type II diabetes mellittus, impaired oral glucose tolerance,elevated blood glucose levels and Syndrome X. The compounds of thepresent invention are further useful as contraceptives and forminimizing the side effects of cyclic menstrual bleeding (e.g. for thetreatment of premenstrual syndrome).

BACKGROUND OF THE INVENTION

Intracellular receptors are a class of structurally related proteinsinvolved in the regulation of gene proteins. Steroid receptors are asubset of these receptors, including the progesterone receptors (PR),androgen receptors (AR), estrogen receptors (ER), glucocorticoidreceptors (GR) and mineralocorticoid receptors (MR). Regulation of agene by such factors requires the intracellular receptor andcorresponding ligands, which has the ability to selectively bind to thereceptor in a way that affects gene transcription.

Progesterone receptor modulators (progestagens) are known to play animportant role in mammalian development and homeostasis. Progesterone isknown to be required for mammary gland development, ovulation and themaintenance of pregnancy. Currently, steroidal progestin agonists andantagonists are clinically approved for contraception, hormonereplacement therapy (HRT) and therapeutic abortion. Moreover, there isgood preclinical and clinical evidence for the value of progestinantagonists in treating endometriosis, uterine leiomyomata (fibroids),dysfunctional uterine bleeding and breast cancer.

The current steroidal progestagens have been proven to be quite safe andare well tolerated. Sometimes, however, side effects (e.g. breasttenderness, headaches, depression and weight gain) have been reportedthat are attributed to these steroidal progestagens, either alone or incombination with estrogenic compounds.

Steroidal ligands for one receptor often show cross-reactivity withother steroidal receptors. As an example, many progestagens also bind toglucocorticoid receptor. Non-steroidal progestagens have no molecularsimilarity with steroids and therefore one might also expect differencesin physicochemical properities, pharmacokinetic (PK) parameters, tissuedistribution (e.g. CNS versus peripheral) and, more importantly,non-steroidal progestagens may show no/less cross-reactivity to othersteroid receptors. Therefore, non-steroidal progestagens will likelyemerge as major players in reproductive pharmacology in the foreseeablefuture.

It was known that progesterone receptor existed as two isoforms,full-length progesterone receptor isoform (PR-B) and its shortercounterpart (PR-A). Recently, extensive studies have been implemented onthe progesterone receptor knockout mouse (PRKO, lacking both the A- andB-forms of the receptors), the mouse specifically lacking both the PR-Aisoform (PRAKO) and the PR-B isoform (PRBKO). Different phenotypes werediscovered for PRKO, PRAKO and PRBKO in physiology studies in terms offertility, ovulation uterine receptivity, uterine proliferation,proliferation of mammary gland, sexual receptivity in female mice,sexual activity in male mice and infanticide tendencies in male mice.These findings provided insights for synthetic chemists to construct notonly selective progesterone receptor modulator (SPRM), but also PR-A orPR-B selective progesterone receptor modulator.

Progesterone plays a major role in reproductive health and functioning.Its effects on, for example, the uterus, breast, cervix andhypothalamic-pituitary unit are well established. The actions ofprogesterone as well as progesterone antagonists are mediated by theprogesterone receptor (PR). In the target cell, progesterone produces adramatic change in confirmation of the PR that is associated withtransforming the PR from a non-DNA binding form to one that will bind toDNA. This transformation is accompanied by a loss of associated heatshock proteins and dimerization. The activated PR dimmer then binds tospecific DNA sequences within the promotor region of progesteroneresponsive genes. The agonist-bound PR is believed to activatetranscription by associating with coactivators, which act as bridgingfactors between the receptor and the general transcription machinery.This is followed by increases in the rate of transcription producingagonist effects at the cellular and tissue levels. These progesteronereceptor ligands exhibit a spectrum of activity ranging from pureantagonists to mixed agonists/antagonists.

In 1982, the discovery of compounds that bind to the progesteronereceptor, antagonize the effects of progesterone receptor and antagonizethe effects of progesterone was announced. Although compounds such asestrogens and certain enzyme inhibitors can prevent the physiologicaleffects of endogenous progesterone, the term “antiprogestin” is confinedto those compounds that bind to the progestin receptor. A report fromthe Institute of Medicine (Donaldson, Molly S.; Dorflinger, L.; Brown,Sarah S.; Benet, Leslie Z., Editors, Clinical Applications ofMifepristone (RU 486) and Other antiprogestins, Committee onantiprogestins: Assessing the science, Institute of medicine, NationalAcademy Press, 1993) summarized a number of medical conditions relatedto the effect of antiprogestins. In view of the pivotal role thatprogesterone plays in reproduction, it is not surprising thatantiprogestins could play a part in fertility control, includingcontraception, menses induction and medical termination of pregnancy,but there are many other potential uses that have been supported bysmall clinical or preclinical studies, such as labor and delivery;treatment of uterine leiomyomas (fibroids), treatment of endometriosis;HRT; breast cancers; male contraception, etc.

The effects and uses of progesterone agonists have been wellestablished. In addition, it has been recently shown that certaincompounds structurally related to the known antiprogestins have agonistactivity in certain biological systems (e.g., the classical progestineffects in the estrogen-primed immature rabbit uterus; cf. C. E. Cook etal., Life Sciences, 52, 155-162 (1993)). Such compounds are partialagonists in human cell-derived receptor systems, where they bind to asite distinct from both the progestin and antiprogestin sites (Wagner etal., Proc. Natl. Acad. Sci., 93, 8739-8744 (1996)). Thus the generalclass of antiprogestins can have subclasses, which may vary in theirclinical profiles.

Compounds which mimic some of the effects of progesterone (agonists),antagonize these effects (antagonists, antiprogestins) or exhibit mixedeffects (partial agonists or mixed agonist/antagonist), known asprogesterone receptor modulators (PRMs) can be useful in treating avariety of disease states and conditions. PR agonists have been used infemale contraceptives and in postmenopausal hormone therapy. Recentstudies in women and non-human primates show that PR antagonists mayalso have potential as contraceptive agents and for the treatment ofvarious gynecological and obstetric diseases, including fibroids,endometriosis and, possibly, hormone-dependent cancers. Clinicallyavailable PR agonists and antagonists are steroidal compounds and oftencause various side effects due to their functional interaction withother steroid receptors. Recently, numerous receptor-selectivenon-steroidal PR agonists and antagonists have emerged. Non-steroidal PRantagonists, being structurally distinct from the steroid class, mayhave greater potential for selectivity against other steroid receptors.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of formula (I)

wherein

R¹ is selected from the group consisting of —NR^(A)R^(B), —O—R^(A),—S—R^(A) and —SO₂—R^(A); wherein R^(A) and R^(B) are each independentlyselected from the group consisting of hydrogen and C₁₋₄alkyl;

R² is selected from the group consisting of C₁₋₄alkyl, —C₁₋₄alkyl-OH,halogenated C₁₋₄alkyl, C₂₋₄alkenyl, —C₂₋₄alkenyl-OH, —C₂₋₄alkenyl-CF₃,C₂₋₄alkynyl, —C₂₋₄alkynyl-CF₃, —C₂₋₄alkynyl-phenyl, —C(O)—C₂₋₄alkyl,—C(O)—C₂₋₄alkenyl and —C(O)-phenyl; wherein the phenyl, whether alone oras part of a substituent group, is optionally substituted with one totwo substituents independently selected from the group consisting ofhalogen, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinatedC₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino and di(C₁₋₄alkyl)amino;

R³ is —OH;

alternatively, R² and R³ are taken together with the carbon atom towhich they are bound to form C(O) or 2-(3-methylene-tetrahydro-furanyl);

and pharmaceutically acceptable salts, esters and prodrugs thereof.

The present invention is further directed to compounds of formula (II)

wherein

R¹ is selected from the group consisting of —NR^(A)R^(B), —O—R^(A),—S—R^(A) and —SO₂—R^(A); wherein R^(A) and R^(B) are each independentlyselected from the group consisting of hydrogen and C₁₋₄alkyl;

R² is selected from the group consisting of C₁₋₄alkyl, —C₁₋₄alkyl-OH,halogenated C₁₋₄alkyl, C₂₋₄alkenyl, —C₂₋₄alkenyl-OH, —C₂₋₄alkenyl-CF₃,C₂₋₄alkynyl, —C₂₋₄alkynyl-CF₃, —C₂₋₄alkynyl-phenyl, —C(O)—C₂₋₄alkyl,—C(O)—C₂₋₄alkenyl and —C(O)-phenyl; wherein the phenyl, whether alone oras part of a substituent group, is optionally substituted with one totwo substituents independently selected from the group consisting ofhalogen, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinatedC₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino and di(C₁₋₄alkyl)amino;

and pharmaceutically acceptable salts, esters and prodrugs thereof.

Illustrative of the invention is a pharmaceutical composition whichcomprises a pharmaceutically acceptable carrier and the product preparedaccording to the process described herein. An illustration of theinvention is a pharmaceutical composition made by mixing the productprepared according to the process described herein and apharmaceutically acceptable carrier. Illustrating the invention is aprocess for making a pharmaceutical composition comprising mixing theproduct prepared according to the process described herein and apharmaceutically acceptable carrier.

Exemplifying the invention are methods of treating a disorder mediatedby at least one progesterone receptor comprising administering to asubject in need thereof a therapeutically effective amount of any of thecompounds or pharmaceutical compositions described above.

In another embodiment, the compounds of the present invention are usefulfor the treatment of disorders mediated by at least one glucocorticoidreceptor comprising administering to a subject in need thereof atherapeutically effective amount of any of the compounds orpharmaceutical compositions described above.

In another embodiment, the compounds of the present invention are usefulfor the treatment of a disorder selected from the group consisting ofsecondary amenorrhea; dysfunctional bleeding; uterine leiomyomata;endometriosis; polycystic ovary syndrome; carcinoma of the endometrium,carcinoma of the ovary, carcinoma of the breast, carcinoma of the colon,carcinoma of the prostate, adenocarcinomas of the ovary, adenocarcinomasof the breast, adenocarcinomas of the colon, adenocarcinomas of theprostate, side effects of cyclic menstrual bleeding or forcontraception; comprising administering to a subject in need thereof atherapeutically effective amount of any of the compounds orpharmaceutical compositions described above.

In another embodiment, the compounds of the present invention are usefulfor the treatment of a disorder selected from the group consisting ofType II diabetes mellitus, impaired oral glucose tolerance, elevatedblood glucose levels and Syndrome X; comprising administering to asubject in need thereof a therapeutically effective amount of any of thecompounds or pharmaceutical compositions described above.

Another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament for treating of aprogesterone or glucocorticoid receptor mediated disorder, (treating adisorder selected from (a) secondary amenorrhea; (b) dysfunctionalbleeding; (c) uterine leiomyomata; (d) endometriosis; (e) polycysticovary syndrome; (f) carcinoma of the endometrium, (g) carcinoma of theovary, (h) carcinoma of the breast, (i) carcinoma of the colon, (j)carcinoma of the prostate, (k) adenocarcinomas of the ovary, (l)adenocarcinomas of the breast, (m) adenocarcinomas of the colon, (n)adenocarcinomas of the prostate, (o) side effects of cyclic menstrualbleeding, (p) Type II diabetes mellitus, (q) impaired oral glucosetolerance, (r) elevated blood glucose levels, (s) Syndrome X or (t) forcontraception, in a subject in need thereof) in a subject in needthereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of formula (I) andcompound of formula (II)

wherein R¹, R² and R³ are as herein defined. The compounds of formula(I) of the present invention are useful as progesterone receptormodulators and/or glucocorticoid receptor modulators, useful in thetreatment of disorders including, but not limited to, secondaryamenorrhea; dysfunctional bleeding; uterine leiomyomata; endometriosis;polycystic ovary syndrome; carcinoma of the endometrium, carcinoma ofthe ovary, carcinoma of the breast, carcinoma of the colon, carcinoma ofthe prostate, adenocarcinomas of the ovary, adenocarcinomas of thebreast, adenocarcinomas of the colon, adenocarcinomas of the prostate,side effects of cyclic menstrual bleeding, Type II diabetes mellitus,impaired oral glucose tolerance, elevated blood glucose levels andSyndrome X or for contraception.

In an embodiment of the present invention, R¹ is selected from the groupconsisting of NR^(A)R^(B), —OR^(A), —SR^(A) and —SO₂—R^(A); whereinR^(A) and R^(B) are each independently selected from the groupconsisting of hydrogen and C₁₋₂alkyl.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of NR^(A)R^(B), —OR^(A), —SR^(A) and —SO₂—R^(A);wherein R^(A) and R^(B) are each independently selected from C₁₋₂alkyl.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of —SR^(A); wherein R^(A) is selected from C₁₋₃alkyl,preferably methylthio.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of dimethylamino, methoxy, methylthio andmethylsulfonyl. In another embodiment of the present invention, R¹ isselected from the group consisting of dimethylamino, methoxy andmethylthio.

In an embodiment of the present invention, R² is selected from the groupconsisting of C₁₋₄alkyl, fluorinated C₁₋₄alkyl, —C₁₋₄alkyl-OH,C₂₋₄alkenyl, —C₂₋₄alkenyl-OH, —C₂₋₄alkenyl-CF₃, C₂₋₄alkynyl,—C₂₋₄alkynyl-CF₃, —C₂₋₄alkynyl-phenyl, —C(O)—C₂₋₄alkyl, and—C(O)—C₂₋₄alkenyl; wherein the phenyl is optionally substituted with oneto two substituents independently selected from the group consisting ofhalogen, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy and fluorinatedC₁₋₄alkoxy.

In another embodiment of the present invention, R² is selected from thegroup consisting of fluorinated C₁₋₃alkyl, C₂₋₄alkenyl, —C₂₋₄alkenyl-OH,C₂₋₄alkynyl; —C₂₋₄alkynyl-CF₃, —C₂₋₄alkynyl-phenyl, and—C(O)—C₂₋₄alkenyl; wherein the phenyl is optionally substituted with oneto two substituents independently selected from the group consisting ofhalogen, C₁₋₄alkyl and fluorinated C₁₋₃alkyl.

In another embodiment of the present invention, R² is selected from thegroup consisting of —CF₂—CF₃, —CCH, —CC—CH₃ and —CC-phenyl; wherein thephenyl is optionally substituted with one to two substituent groupsindependently selected from fluoro or C₁₋₄alkyl.

In another embodiment of the present invention, R² is selected from thegroup consisting of —CC-phenyl; wherein the phenyl is optionallysubstituted with one to two substituents independently selected from thegroup consisting of halogen, C₁₋₄alkyl and fluorinated C₁₋₃alkyl.

In another embodiment of the present invention, R² is selected from thegroup consisting of —CF₂—CF₃, —CH(═CH₂)—CH₃, —CH₂—CH═CH₂, —CCH, —CC—CH₃,—CC—CF₃, —CC-phenyl, —CC-(4-trifluoromethyl-phenyl),—CC-(4-t-butyl-phenyl), —CC-(2-fluor-phenyl), —CC-(3-fluoro-phenyl),—CC-(4-fluoro-phenyl), —CC-(3,5-difluoro-phenyl), —CH(═CH₂)—CH₂—CH₂—OHand —C(O)—CH═CH₂.

In another embodiment of the present invention, R² is selected from thegroup consisting of —CF₂—CF₃, —CH(═CH₂)—CH₃, —CCH, —CC-phenyl,—CC-(2-fluoro-phenyl), —CC-(4-fluoro-phenyl) and—CC-(4-trifluoromethyl-phenyl). In another embodiment of the presentinvention, R² is selected from the group consisting of —CF₂—CF₃,—CH(═CH₂)—CH₃, —CCH and —CC—CH₃.

In an embodiment of the present invention, R² and R³ are taken togetherwith the carbon atom to which they are bound to form C(O) or2-(3-methylene-tetrahydro-furanyl). In another embodiment of the presentinvention, R² and R³ are taken together with the carbon atom to whichthey are bound to form 2-(3-methylene-tetrahydro-furanyl).

In another embodiment of the present invention is any single compound orsubset of compounds selected from the representative compounds listed inTables 1 below.

Additional embodiments of the present invention, include those whereinthe substituents selected for one or more of the variables definedherein (i.e., R¹, R² and R³) are independently selected to be anyindividual substituent or any subset of substituents selected from thecomplete list as defined herein.

Representative compounds of the present invention are as listed in Table1.

TABLE 1 Representative Compounds of Formula (I) and Formula (II)Compound No. Structure 1

2

3

4

5

6

7

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

As used herein, “halogen” shall mean chlorine, bromine, fluorine andiodine.

As used herein, the term “alkyl” whether used alone or as part of asubstituent group, include straight and branched chains. For example,alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, t-butyl, pentyl and the like. Unless otherwisenoted, “C₁₋₄alkyl” shall mean a carbon chain composition of 1-4 carbonatoms.

As used herein, the term “alkenyl” whether used alone or as part of asubstituent group, include straight and branched chains comprising atleast one unsaturated double bond (preferably one to two, morepreferably one unsaturated double bond). For example, alkenyl radicalsinclude —CH═CH₂, 2-propenyl, 3-propenyl, 2-butenyl, 3-butenyl, and thelike. Unless otherwise noted, “C₁₋₄alkenyl” shall mean an alkenyl carbonchain composition of 1-4 carbon atoms.

As used herein, the term “alkynyl” whether used alone or as part of asubstituent group, include straight and branched chains. For example,alkenyl radicals include —C≡CH, 2-propynyl, 3-propynyl, 2-butynyl,3-butynyl, and the like. Unless otherwise noted, “C₁₋₄alkynyl” shallmean an alkynyl carbon chain composition of 1-4 carbon atoms.

As used herein, unless otherwise noted, the term “halogenated C₁₋₄alkyl”shall mean any C₁₋₄alkyl group as defined above substituted with atleast one halogen atom, preferably substituted with a least one fluoroatom. Suitable examples include but are not limited to —CF₃, —CH₂—CF₃,—CF₂—CF₂—CF₂—CF₃, and the like.

As used herein, unless otherwise noted, the term “fluorinated C₁₋₄alkyl”shall mean any C₁₋₄alkyl group as defined above substituted with atleast one fluorine atom, preferably substituted with a least one fluoroatom. Suitable examples include but are not limited to —CF₃, —CH₂—CF₃,—CF₂—CF₂—CF₂—CF₃, and the like.

As used herein, unless otherwise noted, “alkoxy” shall denote an oxygenether radical of the above described straight or branched chain alkylgroups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy,n-hexyloxy and the like.

As used herein, unless otherwise noted, the term “halogenatedC₁₋₄alkoxy” shall mean any C₁₋₄alkoxy group as defined above substitutedwith at least one halogen atom, preferably substituted with a least onefluoro atom. Suitable examples include but are not limited to —OCF₃,—OCH₂—CF₃, —OCF₂—CF₂—CF₂—CF₃, and the like.

As used herein, unless otherwise noted, the term “fluorinatedC₁₋₄alkoxy” shall mean any C₁₋₄alkoxy group as defined above substitutedwith at least one fluorine atom, preferably substituted with a least onefluoro atom. Suitable examples include but are not limited to —OCF₃,—OCH₂—CF₃, —OCF₂—CF₂—CF₂—CF₃, and the like.

As used herein, the notation “*” shall denote the presence of astereogenic center.

When a particular group is “substituted” (e.g., phenyl, aryl,heterocycloalkyl, heteroaryl), that group may have one or moresubstituents, preferably from one to five substituents, more preferablyfrom one to three substituents, most preferably from one to twosubstituents, independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows:

DCE = Dichloroethane DMF = N,N-Dimethylformamide DMSO =Dimethylsulfoxide Et₃N = Triethylamine EtOAc = Ethyl acetate EtOH =Ethanol FBS = Fetal Bovine Serum HPLC = High Pressure LiquidChromatography MeOH = Methanol n-BuLi = n-Butyl Lithium NMO =4-Methylmorpholine N-oxide PR = Progesterone Receptor TBS =tert-Butyldimethylsilyl TBSCl = tert-Butyldimethylchlorosilane TBSOTf =tert-Butyldimethylsilyl trifluoromethanesulphonate TES = TriethylsilylTf = Triflate (i.e. —O—SO₂—CF₃) Tf₂O = Triflic Anhydride THF =Tetrahydrofuran TIPS = Triisopropylsilyl TsCl = Tosic chloride TsOH =Tosic acid

As sued herein, unless otherwise noted, the term “disorder mediated byat least one progesterone receptor” shall include any disorder whosesymptoms and/or underlying cause may be mediated, treated or preventedby the agonism or antagonism of at least one progesterone receptor.Suitable examples include, butt are not limited secondary amenorrhea;dysfunctional bleeding; uterine leiomyomata; endometriosis; polycysticovary syndrome; carcinoma of the endometrium, carcinoma of the ovary,carcinoma of the breast, carcinoma of the colon, carcinoma of theprostate, adenocarcinomas of the ovary, adenocarcinomas of the breast,adenocarcinomas of the colon, adenocarcinomas of the prostate, sideeffects of cyclic menstrual bleeding, and the like. Compounds of thepresent invention which modulate at least one progesterone receptor arefurther useful as contraceptives.

As used herein, unless otherwise noted, the term “disorder mediated byat least one glucocorticoid receptor” shall include any disorder whosesymptoms and/or underlying cause may be mediated, treated or preventedby the agonism or antagonism of at least one progesterone receptor.Suitable examples include, butt are not limited Type II diabetesmellitus, impaired oral glucose tolerance, elevated glucose levels,Syndrome X, and the like.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Preferably, wherein the compound is present as an enantiomer, theenantiomer is present at an enantiomeric excess of greater than or equalto about 80%, more preferably, at an enantiomeric excess of greater thanor equal to about 90%, more preferably still, at an enantiomeric excessof greater than or equal to about 95%, more preferably still, at anenantiomeric excess of greater than or equal to about 98%, mostpreferably, at an enantiomeric excess of greater than or equal to about99%. Similalry, wherein the compound is present as a diastereomer, thediastereomer is present at an diastereomeric excess of greater than orequal to about 80%, more preferably, at an diastereomeric excess ofgreater than or equal to about 90%, more preferably still, at andiastereomeric excess of greater than or equal to about 95%, morepreferably still, at an diastereomeric excess of greater than or equalto about 98%, most preferably, at an diastereomeric excess of greaterthan or equal to about 99%.

Furthermore, some of the crystalline forms for the compounds of thepresent invention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe present invention may form solvates with water (i.e., hydrates) orcommon organic solvents, and such solvates are also intended to beencompassed within the scope of this invention.

Compounds of formula (I) of the present invention may be preparedaccording to the processes outlined in Schemes 1 and 2 below. Compoundsof formula (I) wherein R³ is —OH may be prepared according to theprocedure outlined in Scheme 1 below.

Accordingly, a suitably substituted compound of formula (X), a knowncompound or compound prepared by known methods, is reacted with asuitably selected oxidizing agent such as DMSO/(COCl)₂/Et₃N (swernOxidation), KMnO₄, CrO₃, and the like, in an organic solvent such asmethylene chloride, CHCl₃, and the like, at a temperature in the rangeof from about −78° C. to about 40° C., to yield the correspondingcompound of formula (XI).

The compound of formula (X) is reacted with ethane-1,2-diol, a knowncompound, in the presence of a such as ethylorthoformate, methyl orthoformate, and the like, in the presence of an acid such as TsOH, H₂SO₄,HCl, and the like, in an organic solvent such as THF, dioxane, diethylether and the like, to yield the corresponding compound of formula(XII).

The compound of formula (XII) is reacted with a suitably selectedoxidizing reagent such as OsO₄ and NMO, (CH₃)₃NO, and the like, in anorganic solvent such as butanol, THF, water, and the like, or mixturethereof, to yield the corresponding compound of formula (XIII).

The compound of formula (XIII) is reacted with a suitably selectedoxidizing agent such as lead acetate, NaIO₄, and the like, in an organicsolvent such as THF, dioxane, diethyl ether, and the like, to yield thecorresponding compound of formula (XIV).

The compound of formula (XIV) is reacted with a reducing agent such asNaBH₄, Zn(BH₄)₂, borane, and the like, in an organic solvent such asTHF, diethyl ether, dioxane, and the like, at a temperature in the rangeof from about −10° C. to about room temperature, to yield thecorresponding compound of formula (XV).

The compound of formula (XV) is reacted with a suitably selectedprotecting agent such as TBSCl TBSOTf, and the like, in the presence ofa base such as pyridine, 2,6-lutidine, and the like, in an organicsolvent such as DCM, CHCl₃, 1,2-dicholorethane, and the like, at atemperature in the range of form about 0° C. to about −78° C., to yieldthe corresponding compound of formula (XVI).

The compound of formula (XVI) is reacted under suitably selectedoxidizing conditions such as Dess Martin per iodine reagent, Sweroxidation, Jones oxidation, and the like, in an organic solvent such asDCM, CHCl₃, 1,2dichloroethane, and the like, to yield the correspondingcompound of formula (XVII).

The compound of formula (XVII) is reacted with a suitably substitutedGrignard reagent, a compound of formula (XVIII), a known compound orcompound prepared by known methods, in an organic solvent such as THF,diethyl ether, THF, and the like, at a temperature in the range of fromabout −78° C. to about −10° C., to yield the corresponding compound offormula (XIX).

The compound of formula (XIX) is de-protected by reacting with asuitably selected reagent such as tetrabutyl ammonium fluoride, KF,HF·pyridine/pyridine, and the like, in an organic solvent such as THF,diethyl ether, dioxane, and the like, at a temperature in the range offrom about 0° C. to about room temperature, to yield the correspondingcompound of formula (XX).

The compound of formula (XX) is reacted under acidiccondition, forexample with a catalytic amount of an acid such as TsOH, H₂SO₄, HCl, andthe like in an organic solvent such as THF, acetone, and the like, atroom temperature, to yield the corresponding compound of formula (XXI).

The compound of formula (XXI) is reacted with ethane-1,2-diol, a knowncompound, in the presence of a such as ethylorthoformate, methyl orthoformate, and the like, in the presence of an acid such as TsOH, H₂SO₄,HCl, and the like, in an organic solvent such as THF, dioxane, diethylether, and the like, to yield the corresponding compound of formula(XXII).

The compound of formula (XXII) is reacted with a suitably selectedcompound of formula (XXIII), wherein M is Li, MgCl, MgBr or Mgl, a knowncompound or compound prepared by known methods, in an organic solventsuch as THF, dioxane, diethyl ether, and the like, to yield thecorresponding compound of formula (XXIV).

The compound of formula (XXIV) is reacted with an acid such as TsOH,HCl, sulfiric acid, and the like, in an organic solvent such as THF,acetonitrile, MeOH, EtOH, and the like, to yield the correspondingcompound of formula (Ia).

Compounds of formula (I wherein R² and R³ are taken together with thecarbon atom to which they are bound to form2-(3-mehylene-tetrahydro-furanyl) may be prepared according to theprocess outlined in Scheme 2 below.

Accordingly, a suitably substituted compound of formula (XXII), acompound prepared, for example, as described Scheme 1 above, is reactedwith a suitably substituted compound of formula (XV), wherein W is aprotecting group such as TBS, TES, TIPS, and the like, a known compoundor compound prepared by known methods, in an organic solvent such asTHF, dioxane, diethyl ether, and the like, at a temperature in the rangeof from about −10° C. to about 30° C., to yield the correspondingcompound of formula (XXVI).

The compound of formula (XXVI) is cyclized by reacting with a reagentsuch as methane sulphonyl chloride, TsCl, Tf₂O, and the like, in thepresence of a phase transfer catalyst such as tetrabutyl amooniumfluoride and the like, preferably in the presence of from about one toabout 30 equivalents of pyridine, in an organic solvent such as THF,diethyl ether, dioxane, and the like, to yield the correspondingcompound of fomrula (XXVII).

The compound of formula (XXVII) is reacted with an acid such as TsOH,HCl, H₂SO₄, and the like, in an organic solvent such as acetone, THF,dioxane, and the like, at a temperature in the range of from about 0° C.to about room temperature, to yield the corresponding compound offormula (Ib).

Compounds of formula (II) may be prepared according to the procedure asoutlined in Scheme 3 below.

Accordingly, a suitably substituted compound of formula (Ia) is reactedwith an acid such as TsOH, HCl, H₂SO₄, and the like, according to knownmethods, to yield the corresponding compound of formula (II).

One skilled in the art will recognize that wherein a reaction step ofthe present invention may be carried out in a variety of solvents orsolvent systems, said reaction step might also be carried out in amixture of the suitable solvents or solvent systems. Where the processesfor the preparation of the compounds according to the invention giverise to mixture of stereoisomers, these isomers may be separated byconventional techniques such as preparative chromatography. Thecompounds may be prepared in racemic form, or individual enantiomers maybe prepared either by enantiospecific synthesis or by resolution. Thecompounds may, for example, be resolved into their component enantiomersby standard techniques, such as the formation of diastereomeric pairs bysalt formation with an optically active acid, such as(−)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acidfollowed by fractional crystallization and regeneration of the freebase. The compounds may also be resolved by formation of diastereomericesters or amides, followed by chromatographic separation and removal ofthe chiral auxiliary. Alternatively, the compounds may be resolved usinga chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts includethe following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

Representative acids and bases which may be used in the preparation ofpharmaceutically acceptable salts include the following:

acids including acetic acid, 2,2-dichloroactic acid, acylated aminoacids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid,benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid,(+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonicacid, capric acid, caproic acid, caprylic acid, cinnamic acid, citricacid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid,ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconicacid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolicacid, hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lacticacid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malicacid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinc acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitric acid, pamoic acid, phosphoric acid,L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid; and

bases including ammonia, L-arginine, benethamine, benzathine, calciumhydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

The present invention further comprises pharmaceutical compositionscontaining one or more compounds of formula (I) and/or one or morecompounds of formula (II) with a pharmaceutically acceptable carrier.Pharmaceutical compositions containing one or more of the compounds ofthe invention described herein as the active ingredient can be preparedby intimately mixing the compound or compounds with a pharmaceuticalcarrier according to conventional pharmaceutical compounding techniques.The carrier may take a wide variety of forms depending upon the desiredroute of administration (e.g., oral, parenteral). Thus for liquid oralpreparations such as suspensions, elixirs and solutions, suitablecarriers and additives include water, glycols, oils, alcohols, flavoringagents, preservatives, stabilizers, coloring agents and the like; forsolid oral preparations, such as powders, capsules and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like. Solidoral preparations may also be coated with substances such as sugars orbe enteric-coated so as to modulate major site of absorption. Forparenteral administration, the carrier will usually consist of sterilewater and other ingredients may be added to increase solubility orpreservation. Injectable suspensions or solutions may also be preparedutilizing aqueous carriers along with appropriate additives.

To prepare the pharmaceutical compositions of this invention, one ormore compounds of the present invention as the active ingredient isintimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, through other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, of from about 50-100 mg and maybe given at a dosage of from about 0.1-5.0 mg/kg/day, preferably fromabout 0.5-2.5 mg/kg/day. The dosages, however, may be varied dependingupon the requirement of the patients, the severity of the conditionbeing treated and the compound being employed. The use of either dailyadministration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 500 mg ofthe active ingredient of the present invention. The tablets or pills ofthe novel composition can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterial can be used for such enteric layers or coatings, such materialsincluding a number of polymeric acids with such materials as shellac,cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The methods of treating of the present invention may also be carried outusing a pharmaceutical composition comprising any of the compounds asdefined herein and a pharmaceutically acceptable carrier. Thepharmaceutical composition may contain between about 0.1 mg and 500 mg,preferably about 50 to 100 mg, of the compound, and may be constitutedinto any form suitable for the mode of administration selected. Carriersinclude necessary and inert pharmaceutical excipients, including, butnot limited to, binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings. Compositions suitable fororal administration include solid forms, such as pills, tablets,caplets, capsules (each including immediate release, timed release andsustained release formulations), granules, and powders, and liquidforms, such as solutions, syrups, elixers, emulsions, and suspensions.Forms useful for parenteral administration include sterile solutions,emulsions and suspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

To prepare a pharmaceutical composition of the present invention, acompound of formula (I) as the active ingredient is intimately admixedwith a pharmaceutical carrier according to conventional pharmaceuticalcompounding techniques, which carrier may take a wide variety of formsdepending of the form of preparation desired for administration (e.g.oral or parenteral). Suitable pharmaceutically acceptable carriers arewell known in the art. Descriptions of some of these pharmaceuticallyacceptable carriers may be found in The Handbook of PharmaceuticalExcipients, published by the American Pharmaceutical Association and thePharmaceutical Society of Great Britain.

Methods of formulating pharmaceutical compositions have been describedin numerous publications such as Pharmaceutical Dosage Forms: Tablets,Second Edition, Revised and Expanded, Volumes 1-3, edited by Liebermanet al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2,edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems,Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment of disorders as described herein is required.

The daily dosage of the products may be varied over a wide range from0.01 to 1,000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250 and 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated. An effectiveamount of the drug is ordinarily supplied at a dosage level of fromabout 0.01 mg/kg to about 300 mg/kg of body weight per day. Preferably,the range is from about 0.5 to about 5.0 mg/kg of body weight per day,most preferably, from about 1.0 to about 3.0 mg/kg of body weight perday. The compounds may be administered on a regimen of 1 to 4 times perday.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

One skilled in the art will recognize that, both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a test compound to treat orprevent a given disorder.

One skilled in the art will further recognize that human clinical trailsincluding first-in-human, dose ranging and efficacy trials, in healthypatients and/or those suffering from a given disorder, may be completedaccording to methods well known in the clinical and medical arts.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products are listed ashaving been isolated as a residue. It will be understood by one ofordinary skill in the art that the term “residue” does not limit thephysical state in which the product was isolated and may include, forexample, a solid, an oil, a foam, a gum, a syrup, and the like.

EXAMPLE 13′H-spiro-[[1,3]-dioxol-11,12-Dihydroxy-13-methyl-1,6,7,8,11,12,13,14,15,16-decahydro-2H-cyclopenta[a]phenanthrene-3,17-dione(Compound #39)

A solution of 1,3dioxolane-13-methyl-1,6,7,8,13,14,15,16-octahydro-2H-cyclopenta[a]phenanthrene-3,17-dione(30 g, 95.54 mmol) in t-butanol (600 mL) was prepared and OsO₄ (1 mL)was added along with NMO (45 gm). The resulting mixture was stirred atroom temperature for 45 hours. Water (600 mL) and EtOAc (1200 mL) wasadded and the layers were separated. The aqueous layer was extractedwith EtOAc (350 mL). The organic layers were washed with water, brine,dried over magnesium sulfate, filtered, and evaporated to dryness. Theresulting sticky oil was suspended in (100 mL) and hexanes (100 mL) andstirred. The solid was filtered and dried in vacuuo to yield the titlecompound.

MS=347.18 (M+H⁺)

EXAMPLE 26′-(2-Formyl-2-methyl-3-oxo-cyclopentyl)-4′,6′,7′,8′-tetrahydro-3′H-spiro-[[1,3]-dioxol-ane-2,2′-naphthalene]-5′-carbaldehyde(Compound #40)

A solution of 1,3 dioxolane, 11-12dihydroxy-13-Methyl-1,6,7,8,13,14,15,16-octahydro-2H-cyclopenta[a]phenanthrene-3,17-dione(15 g, 50.54 mmol) in THF (600 mL) was prepared and lead tetra acetate(28 g) were added along with pyridine (10 mL). The resulting mixture wasstirred at room temperature for 5 hours. Aqueous solution of NaHCO₃ wasadded (600 mL) and EtOAc (1200 mL) was added and the layers wereseparated. The aqueous layer was extracted with EtOAc (350 mL). Theorganic layers were washed with water, brine, dried over magnesiumsulfate, filtered, and evaporated to dryness. The resulting sticky oilwas purified by column chromatography eluting with 20 to 95% ethylacetate/hexanes to yield the title compound as a white solid.

MS=347.18 (M+H⁺)

EXAMPLE 32-Hydroxymethyl-3-(5′-hydroxymethyl-4′,6′,7′,8′-tetrahydro-3′H-spiro[[1,3]dioxolane-2,2′-naphthalen]-6′-yl)-2-methyl-cyclopentanone(Compound #41)

A solution of6′-(2-formyl-2-methyl-3-oxo-cyclopentyl)-4′,6′,7′,8′-tetrahydro-3′H-spiro[[1,3]dioxolane-2,2′-naphthalene]-5′-carbaldehyde(5 g, 10 mmol) in THF (300 mL) was prepared and NaBH₄ (4 g) were addedslowly and stirred at room temperature for 6 hours. Aqueous solution ofNaHCO₃ was added (600 mL) and EtOAc (1200 mL) was added and the layerswere separated. The aqueous layer was extracted with EtOAc (350 mL). Theorganic layers were washed with water, brine, dried over magnesiumsulfate, filtered, and evaporated to dryness. The resulting sticky oilwas purified by column chromatography eluting with 20 to 100% ethylacetate/hexanes to yield the title compound as a white solid.

MS=349.3 (M+H⁺)

EXAMPLE 42-(tert-Butyl-dimethyl-silanyloxymethyl)-3-(5′-hydroxymethyl-4′,6′,7′,8′-tetrahydro-3′H-spiro[[1,3]dioxolane-2,2′-naphthalen]-6′-yl)-2-methyl-cyclopentanone(Compound #42)

A solution of2-hydroxymethyl-3-(5′-hydroxymethyl-4′,6′,7′,8′-tetrahydro-3′H-spiro[[1,3]dioxolane-2,2′naphthalen]-6′-yl)-2-methyl-cyclopentanone(4 g, 10 mmol) in CH₂Cl₂ (300 mL) was prepared and cooled to −78° C. andpyridine (4.1 mL) and TBSOTf (3.3 mL) were added slowly and stirred at−78° C. temperature for 6 hours. An aqueous solution of NaHCO₃ was added(600 mL) and EtOAc (300 mL) was added and the layers were separated. Theaqueous layer was extracted with EtOAc (350 mL). The organic layers werewashed with water, brine, dried over magnesium sulfate, filtered, andevaporated to dryness. The resulting crude compound was purified bycolumn chromatography eluting with 20 to 80% ethyl acetate/hexanes toyield the title compound as a crystalline white solid.

MS=463.4 (M+H⁺)

EXAMPLE 56′-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-2-methyl-3-oxo-cyclopentyl]-4′,6′,7′,8′-tetrahydro-3′H-spiro[[1,3]dioxolane-2,2′-naphthalene]-5′-carbaldehyde(Compound # 43)

A solution of2-(tert-Butyl-dimethyl-silanyloxymethyl)-3-(5′-hydroxymethyl-4′,6′,7′,8′-tetrahydro-3′Hspiro[[1,3]-dioxolane-2,2′-naphthalen]-6′-yl)-2-methyl-cyclopentanone (2g, 10 mmol) in CH₂Cl₂ (100 mL) was prepared and cooled to −10° C. andpyridine (2.1 mL) Dess Martine per iodine (4.8 mg) were added slowly andthe reaction mixture stirred at room temperature for 9 hours. An aqueoussolution of NaHCO₃ was added (600 mL) and EtOAc (300 mL) was added andthe layers were separated. The aqueous layer was extracted with EtOAc(350 mL). The organic layers were washed with water, brine, dried overmagnesium sulfate, filtered, and evaporated to dryness. The resultingcrude compound was purified by column chromatography eluting with 20 to80% ethyl acetate/hexanes to yield the title compound as a crystallinewhite solid.

MS=461.2 (M+H⁺)

EXAMPLE 63′H-spiro[[1,3]dioxolane-10-(4-Dimethylamino-phenyl)-12a-methyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-8H-11-oxa-naphtho[2,1e]azulene-1,7-dione (Compound #44)

Step 1: 2-(tert-Butyl-dimethyl-silanyloxymethyl)-3-{5′-[(4-dimethylamino-phenyl)-hydroxy-methyl]-4′,6′,7′,8′-tetrahydro-3′Hspiro[[1,3]dioxolane-2,2′-naphthalen]-6′-yl}-2-methyl-cyclopentanone

A solution of 6′-[2-(tert-Butyl-dimethyl-silanyloxymethyl)-2-methyl-3-oxo-cyclopentyl]-4′,6′,7′,8′-tetrahydro-3′H-spiro[[1,3]dioxolane-2,2′-naphthalene]-5′-carbaldehyde(1 g, 5 mmol) in THF (50 mL) was prepared and cooled to −78° C. andN,N-dimethyl phenyl magnesium bromide (2.1 mL, 1M solution in THF) wasadded stirred at −78° C. for 9 hours. Aqueous solution of NaHCO₃ wasadded (300 mL) and EtOAc (300 mL) was added and the layers wereseparated. The aqueous layer was extracted with EtOAc (350 mL). Theorganic layers were washed with water, brine, dried over magnesiumsulfate, filtered, and evaporated to dryness. The resulting crudecompound was purified by column chromatography eluting with 20 to 80%ethyl acetate/hexanes to yield the title compound as a crystallineyellow solid.

MS=347.18 (M+H⁺)

¹H NMR (400 MHz, CDCl₃): δ 7.16 (2H, d, J=8.8 Hz), 6.66 (2H, d, J=8.8Hz), 5.46 (1H, s), 5.41 (s, 1H), 3.71 [center of AB quartet,J_(AB)=12.0, Δν=284 Hz, δ_(A)=4.05, δ_(B)=3.34, 2H], 4.15-3.89 (m, 4H),2.92 (6H, s), 2.76-2.69 (m, 1H), 2.59-2.42 (m, 3H), 2.38-2.29 (m, 1H),2.26-2.11 (m, 2H), 2.06-1.91 (m, 2H), 1.89-1.64 (m, 5H), 1.13 (3H, s).

Step 2

A solution of2-(tert-butyl-dimethyl-silanyloxymethyl)-3-{5′-[(4-dimethylamino-phenyl)-hydroxy-methyl]-4′,6′,7′,8′-tetrahydro-3′H-spiro[[1,3]dioxolane-2,2′-naphthalen]-6′-yl}-2-methyl-cyclopentanone(1 g, 5.6 mmol) in THF (50 mL) was prepared and cooled to −10° C. andthen tetra butyl ammonium fluoride (6.1 mL) was added and the resultingmixture was stirred at −10° C. for 12 hours. An aqueous solution ofNaHCO₃ was added (300 mL) and EtOAc (300 mL) was added and the layerswere separated. The aqueous layer was extracted with EtOAc (350 mL). Theorganic layers were washed with water, brine, dried over magnesiumsulfate, filtered, and evaporated to dryness. The resulting crudecompound was purified by column chromatography eluting with 20 to 80%ethyl acetate/hexanes to yield the3-{5′-[(4-Dimethylamino-phenyl)-hydroxy-methyl]-4′,6′,7′,8′-tetrahydro-3′Hspiro[[1,3]dioxolane-2,2′-naphthalen]-6′-yl}-2-hydroxymethyl-2methylcyclopenta-nonecompound as a crystalline yellow solid.

MS=467.2 (M+H⁺)

Step 3

A solution of3-{5′-[(4-dimethylamino-phenyl)-hydroxy-methyl]-4′,6′,7′,8′-tetrahydro-3′H-spiro[[1,3]dioxolane-2,2′-naphthalen]-6′-yl}-2-hydroxymethyl-2-methyl-cyclopentanone(1 g, 5.6 mmol) in THF (50 mL) was prepared and cooled to 0° C. and thenTsOH (0.1 g) was added and stirred at room temperature for 14 hours. Anaqueous solution of NaHCO₃ was added (300 mL) and EtOAc (300 mL) wasadded and the layers were separated. The aqueous layer was extractedwith EtOAc (350 mL). The organic layers were washed with water, brine,dried over magnesium sulfate, filtered, and evaporated to dryness. Theresulting crude compound was purified by column chromatography elutingwith 20 to 80% ethyl acetate/hexanes to yield the title compound as acrystalline yellow solid.

MS=450.56 (M+H⁺)

EXAMPLE 710-(4-Dimethylamino-phenyl)-1-hydroxy-12a-methyl-1-prop-1-ynyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #7)

Step 1

A solution of2-(tert-Butyl-dimethyl-silanyloxymethyl)-3-{5′-[(4-dimethylamino-phenyl)-hydroxy-methyl]-4′,6′,7′,8′-tetrahydro-3′H-spiro[[1,3]dioxolane-2,2′-naphthalen]-6′-yl}-2-methyl-cyclopentanone(1 g, 5.6 mmol) in THF (50 mL) was prepared and cooled to 0° C. and thenTsOH (0.1 g) was added and the resulting mixture stirred at roomtemperature for 14 hours. An aqueous solution of NaHCO₃ was added (300mL) and EtOAc (300 mL) was added and the layers were separated. Theaqueous layer was extracted with EtOAc (350 mL). The organic layers werewashed with water, brine, dried over magnesium sulfate, filtered, andevaporated to dryness. The resulting crude compound was purified bycolumn chromatography eluting with 20 to 80% ethyl acetate/hexanes toyield the3′H-spiro[[1,3]dioxolane-10-(4-Dimethylamino-phenyl)-1-hydroxy-12a-methyl-1-prop-1-ynyl2,3,3a,3b,4,5,9,10,12,12adeca hydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one compound as acrystalline yellow solid.

MS=490.2 (M+H⁺)

Step 2

3-′H-spiro[[1,3]dioxolane-10-(4-Dimethylamino-phenyl)-1-hydroxy-12a-methyl-1-prop-1-ynyl2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(200 mg) in acetone (5 mL) was prepared and cooled to 0° C. and thenTsOH (0.001 g) was added and the resulting mixture stirred at roomtemperature for 5 hours. An aqueous solution of NaHCO₃ was added (100mL) and EtOAc (100 mL) was added and the layers were separated. Theaqueous layer was extracted with EtOAc (50 mL). The organic layers werewashed with water, brine, dried over magnesium sulfate, filtered, andevaporated to dryness. The resulting crude compound was purified bycolumn chromatography eluting with 20 to 80% ethyl acetate/hexanes toyield the title compound as a crystalline yellow solid.

MS=446.2(M+H⁺)

EXAMPLE 8 (Compound #38)

Step 1

A solution of tert-butyl-(3-iodo-but-3-enyloxy)-dimethyl-silane (312 mg,1 mmol) in THF (5 mL) was prepared and cooled to −78° C. and n-BuLi (3.5mL, 1.6 M solution in hexanes) was added. The resulting mixture wasstirred at −78° C. for 3 min. To the reaction mixture was then added asolution of3′H-spiro[[1,3]dioxolane-10-(4-dmethylamino-phenyl)-12a-methyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-8H-11-oxa-naphtho[2,1-e]azulene-1,7-dione(120 mg in 5 ml of THF) and the mixture stirred for 30 min. An aqueoussolution of NaHCO₃ was added (300 mL) and EtOAc (300 mL) was added andthe layers were separated. The aqueous layer was extracted with EtOAc(350 mL). The organic layers were washed with water, brine, dried overmagnesium sulfate, filtered, and evaporated to dryness. The resultingcrude compound was purified by column chromatography eluting with 20 to80% ethyl acetate/hexanes to yield the1-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-vinyl}-10-(4-dimethylamino-phenyl)-1-hydroxy-12a-methyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one.asa crystalline yellow solid.

MS=636.2 (M+H⁺)

Step 2

The compound prepared in Step 1 above (1 g, 5.6 mmol) in THF:pyridine (5ml:5 mL) was prepared and cooled to −10° C. and tetra butyl ammoniumfluoride (6.1 mL) was added and and the resulting mixture stirred at−10° C. for 0.5 hours. Methane sulphonyl chloride (100 □L) was added andthe resulting mixture stirred for additional 3 hours. An aqueoussolution of NaHCO₃ was added (50 mL) and EtOAc (100 mL) was added andthe layers were separated. The aqueous layer was extracted with EtOAc(50 mL). The organic layers were washed with water, brine, dried overmagnesium sulfate, filtered, and evaporated to dryness. The resultingcrude compound was purified by column chromatography eluting with 20 to80% ethyl acetate/hexanes to yield the title compound as a crystallineyellow solid.

MS=503.30 (M+H⁺)

Step 3

The compound prepared in Step 2 above (200 mg) was dissolved in acetone(5 mL) was prepared and cooled to 0° C., then TsOH (0.001 g) was addedand the resulting mixture stirred at room temperature for 5 hours. Anaqueous solution of NaHCO₃ was added (100 mL) and EtOAc (100 mL) wasadded and the layers were separated. The aqueous layer was extractedwith EtOAc (50 mL). The organic layers were washed with water, brine,dried over magnesium sulfate, filtered, and evaporated to dryness. Theresulting crude compound was purified by column chromatography elutingwith 20 to 80% ethyl acetate/hexanes to yield the title compound as acrystalline yellow solid.

MS=446.2 (M+H⁺)

EXAMPLE 9 10-(4-Dimethylamino-phenyl)-1-hydroxy-1-isopropenyl-12amethyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1e]azulen-7-one (Compound #1)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 8.

MS=460 (M+H⁺)

EXAMPLE 10 3′H-spiro[[1,3]dioxolane12a-Methyl-10-(4-methylsulfanyl-phenyl)2,3,3a,3b,4,5,9,10,12,12a-decahydro-8H-11-oxa-naphtho[2,1-e]azulene-1,7dione (Compound #51)

The title compound was prepared as a white solid according to theprocedure described in Example 6, 7 and 8 above, starting from thecompound prepared as in Example 5.

MS=453 (M+H⁺)

EXAMPLE 11 3′H-spiro[[1,3]dioxolane12a-Methyl-10-(4-methoxy-phenyl)2,3,3a,3b,4,5,9,10,12,12a-decahydro-8H-11-oxa-naphtho[2,1-e]azulene-1,7dione (Compound #45)

The title compound was prepared as a white solid according to theprocedure described in Example 6, starting from the compound prepared asin Example 5.

MS=437.2 (M+H⁺)

¹H NMR (400 MHz, CDCl₃): δ 7.15 (2H, d, J=8.8 Hz), 6.67 (2H, d, J=8.8Hz), 5.77 (1H, s), 5.39 (1H, s), 5.09 (1H, s), 4.84 (1H, s), 3.85-3.77(3H, m), 3.21 (1H, part of AB quartet), 2.93 (6H, s), 2.88-2.82 (1H, m),2.71-2.51 (4H, m), 2.48-2.33 (3H, m), 2.31-2.22 (1H, m), 2.18-2.04 (2H,m), 1.98-1.78 (3H, m), 1.71-1.63 (m, 2H), 1.18 (s, 3H)

EXAMPLE 121-Hydroxy-1-isopropenyl-12a-methyl-10-(4-methylsulfanyl-phenyl)-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #2)

The title compound was prepared as a white solid according to theprocedure described in Example 6 starting from the compound prepared asin Example 8.

MS=451.2 (M+H⁺)

EXAMPLE 13 (Compound #2)

The title compound was prepared as a white solid according to theprocedure described in Example 8, starting from the compound prepared asin Example 9.

MS=447.25 (M+H⁺)

¹H NMR (400 MHz, CDCl₃): δ 7.15 (2H, d, J=8.8 Hz), 6.67 (2H, d, J=8.8Hz), 5.77 (1H, s), 5.39 (1H, s), 5.09 (1H, s), 4.84 (1H, s), 3.85-3.77(3H, m), 3.21 (1H, part of AB quartet), 2.93 (6H, s), 2.88-2.82 (1H, m),2.71-2.51 (4H, m), 2.48-2.33 (3H, m), 2.31-2.22 (1H, m), 2.18-2.04 (2H,m), 1.98-1.78 (3H, m), 1.71-1.63 (m, 2H), 1.18 (s, 3H).

EXAMPLE 1410-(4-Dimethylamino-phenyl)-1-ethynyl-1-hydroxy-12a-methyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #3)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 6.

MS=432.25 (M+H⁺)

EXAMPLE 151-Hydroxy-12a-methyl-10-(4-methylsulfanyl-phenyl)-1-pentafluoroethyl-2,3,3a,3b4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #4)

The title compound was prepared as a white solid according to theprocedure described in Example 7, starting from the compound prepared asin Example 6 and reacting with LiCF₂CF₃.

MS=528.18

EXAMPLE 161-Hydroxy-10-(4-methoxy-phenyl)-12a-methyl-1-(4-trifluoromethyl-phenylethynyl)-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #6)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 8.

MS=563.2

EXAMPLE 171-(4-tert-Butyl-phenylethynyl)-1-hydroxy-10-(4-methoxy-phenyl)-12a-methyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #9)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 8.

MS=551.2

EXAMPLE 1810-(4-Dimethylamino-phenyl)-12a-methyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-8H-11-oxa-naphtho[2,1-e]azulene-1,7-dione(Compound #10)

3′H-spiro[[1,3]dioxolane-10-(4-Dimethylamino-phenyl)-1,2a-methyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-8H-11-oxa-naphtho[2,1e]azulene-1,7-dione,prepared as in Example 6 above (50 mg) was dissolved in acetone (5 mL)was prepared and cooled to 0° C. TsOH (0.001 g) was added and theresulting mixture stirred at room temperature for 5 hours. An aqueoussolution of NaHCO₃ was added (100 mL) and EtOAc (100 mL) was added andthe layers were separated. The aqueous layer was extracted with EtOAc(50 mL). The organic layers were washed with water, brine, dried overmagnesium sulfate, filtered, and evaporated to dryness. The resultingcrude compound was purified by column chromatography eluting with 20 to80% ethyl acetate/hexanes to yield the title compound as a crystallineyellow solid.

MS=406.2 (M+H⁺)

EXAMPLE 19 12a-Methyl-10-(4-methylsulfanyl-phenyl)-1-phenylethynyl3a,3b,4,5,9,10,12,12a-octahydro-3H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #11)

The title compound was prepared as a white solid according to theprocedure described in Example 17 starting from the compound prepared asin Example 10.

MS=493.2

EXAMPLE 201-Ethynyl-1-hydroxy-10-(4-methoxy-phenyl)-12a-methyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #12)

The title compound was prepared as a white solid according to theprocedure described in Example 17 starting from the compound prepared asin Example 11.

MS=419.3

¹H NMR (300 MHz, CDCl₃): δ 7.25 (2H, d, J=8.8 Hz), 6.85 (2H, d, J=8.8Hz), 5.80 (1H, s), 5.55 (1H, s), 3.79 (3H, s), 3.95-3.60 (AB quartet,J_(AB)=12.0, 2H), 2.80-1.60 (14H, m), 2.60 (1H, s), 1.12 (3H, s).

EXAMPLE 21 3′H-spiro[[1,3]dioxolane-10-α-(4-Methoxy-phenyl)-12a-methyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-8H-11-oxa-naphtho[2,1-e]azulene-1,7-dione

The title compound was isolated as side product as in preparationdescribed in Example 11

MS 437.2

EXAMPLE 22 1-Ethynyl-1-hydroxy-10-(4-methoxy-phenyl)-12a-methyl2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #13)

The title compound was prepared as a white solid according to theprocedure described in Example 17 starting from the compound prepared asin Example 21.

MS=419.3

¹H NMR (300 MHz, CDCl₃): δ 7.25 (2H, d, J=8.8 Hz), 6.85 (2H, d, J=8.8Hz), 6.05 (1H, s), 5.75 (1H, s), 3.81 (3H, s), 3.80-3.20 (AB quartet,J_(AB)=12.0, 2H), 2.80-1.60 (14H, m), 2.55 (1H, s), 1.10 (3H, s).

EXAMPLE 231-Hydroxy-10-(4-methoxy-phenyl)-12a-methyl-1-prop-1-ynyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one:(Compound #14)

The title compound was prepared as a white solid according to theprocedure described in Example 7, starting from the compound prepared asin Example 11.

MS=433.3

¹H NMR (300 MHz, CDCl₃): δ 7.25 (2H, d, J=8.8 Hz), 6.85 (2H, d, J=8.8Hz), 5.70 (1H, s), 5.56 (1H, s), 3.69 (3H, s), 3.90-3.50 (AB quartet,J_(AB)=12.0, δ_(A)=3.90, δ_(B)=3.60, 2H], 2.85-1.60 (14H, m), 1.70 (3H,s), 1.10 (3H, s).

EXAMPLE 241-Hydroxy-10-α(4-methoxy-phenyl)-12a-methyl-1-prop-1-ynyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #15)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 21.

MS=433.2

¹H NMR (300 MHz, CDCl₃): δ 7.28 (2H, d, J=8.8 Hz), 6.91 (2H, d, J=8.8Hz), 6.05 (1H, s), 5.61 (1H, s), 3.79 (3H, s), 3.50 [center of ABquartet, J_(AB)=12.0, Δν=180 Hz, δ_(A)=3.80, δ_(B)=3.20, 2H], 2.71-1.52(14H, m), 1.49 (3H, s), 1.10 (3H, s).

EXAMPLE 251-Hydroxy-10-(4-methoxy-phenyl)-12a-methyl-1-phenylethynyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #16)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 11.

MS=495.2

EXAMPLE 26 1-Allyl-1-hydroxy-10-(4-methoxy-phenyl)-12a-methyl2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #17)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 11.

MS=435.2

¹H NMR (300 MHz, CDCl₃): δ 7.25 (2H, d, J=8.8 Hz), 6.88 (2H, d, J=8.8Hz), 6.05-5.80 (1H, m), 5.79 (1H, s), 5.51 (1H, s), 5.25-5.15 (2H, m),3.91-3.48 (AB quartet, J_(AB)=12.0, 2H), 3.80 (3H, s), 2.90-2.80 (1H,m), 2.60-1.60 (13H, m), 1.20 (3H, s).

EXAMPLE 27 1-Allyl-1-hydroxy-10α-(4-methoxy-phenyl)-12a-methyl2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #18)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 21.

MS=435.2

¹H NMR (300 MHz, CDCl₃): δ 7.25 (2H, d, J=8.8 Hz), 6.90 (2H, d, J=8.8Hz), 6.05 (1H, s), 5.72 (1H, s), 5.81-5.68 (1H, m), 5.10 (1H, dd, J=1.2,6.8 Hz), 4.95 (1H, dd, J=1.2, 12.0 Hz), 3.81 (3H, s), 3.40-3.15 (ABquartet, J_(AB)=12.0, 2H), 2.85-2.71 (1H, m), 2.60-1.60 (13H, m), 1.18(3H, s).

EXAMPLE 281-Hydroxy-10-(4-methoxy-phenyl)-12a-methyl-1-trifluoroprop-1-ynyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #19)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 11.

MS=487.4 (M+H⁺)

EXAMPLE 291-Hydroxy-10-□-(4-methoxy-phenyl)-12a-methyl-1-trifluoroprop-1-ynyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #20)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 21.

MS=487.4 (M+H⁺)

¹H NMR (400 MHz, CDCl₃): δ 7.22 (2H, d, J=8.8 Hz), 6.89 (2H, d, J=8.8Hz), 6.10 (1H, s), 5.80 (1H, s), 3.82 (3H, s), 3.33 [center of ABquartet, J_(AB)=12.4, Δν=109 Hz, δ_(A)=3.46, δ_(B)=3.19, 2H], 2.92-1.61(14H, m), 1.15 (3H, s).

EXAMPLE 30 1-Hydroxy-10-(4-methoxy-phenyl)-12a-methyl-1-(4-trifluoromethylphenylethynyl)-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #21)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 11.

MS=563.4 (M+H⁺)

EXAMPLE 31 1-Hydroxy-10-(4-methoxy-phenyl)-12a-methyl-1-(4-trifluoromethylphenylethynyl)-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #22)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 21.

MS=563.4 (M+H⁺)

EXAMPLE 321-Hydroxy-10-(4-methoxy-phenyl)-12a-methyl-1-phenylethynyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #23)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 21.

MS=495.4 (M+H⁺)

¹H NMR (300 MHz, CDCl₃): δ 7.39-7.20 (7H, m), 6.88 (2H, d, J=8.8 Hz),5.80 (1H, s), 5.60 (1H, s), 4.02-3.56 (AB quartet, J_(AB)=12.0, 2H),3.80 (3H, s), 2.90-1.60 (14H, m), 1.20 (3H, s).

EXAMPLE 331-Hydroxy-1-[2-(2-hydroxy-ethyl)-allyl]-10-(4-methoxy-phenyl)-12a-methyl-2,3,3a3b4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one

Step 1

A solution of tert-butyl-(3-iodo-but-3-enyloxy)-dimethyl-silane (312mg,) in THF (5 mL) was prepared and cooled to −78° C. and then n-BuLi(3.5 ml, 1.6 M solution in hexanes) was added and the resulting mixturestirred at −78° C. for 3 min. To the reaction mixture was then added asolution of 3′H-spiro[[1,3]dioxolane-10-(4-4methoxy-phenyl)-12a-methyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-8H-11-oxa-naphtho[2,1-e]azulene-1,7-dione(120 mg in 5 ml of THF) and the resulting mixture was stirred for 30min. An aqueous solution of NaHCO₃ was added (300 mL) and EtOAc (300 mL)was added and the layers were separated. The aqueous layer was extractedwith EtOAc (350 mL). The organic layers were washed with water, brine,dried over magnesium sulfate, filtered, and evaporated to dryness. Theresulting crude compound was purified by column chromatography elutingwith 20 to 80% ethyl acetate/hexanes to yield the 3′H-spiro[1,3]dioxolane-1-{2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-allyl}-1-hydroxy-10-(4-methoxy-phenyl)-12a-methyl-2,3,3a,3b,4,5,9,10,12,12adecahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one as a crystallineyellow solid.

Step 2

A solution of 3′H-spiro[1,3]dioxolane-1-{2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-allyl}-1-hydroxy-10-(4-methoxy-phenyl)-12a-methyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(0.1 g) in THF (50 mL) was prepared and cooled to −10° C. Tetra butylammonium fluoride (1.3 mL) was added and the resulting mixture wasstirred at −10° C. for 12 hours. An aqueous solution of NaHCO₃ was added(30 mL) and EtOAc (300 mL) was added and the layers were separated. Theaqueous layer was extracted with EtOAc (35 mL). The organic layers werewashed with water, brine, dried over magnesium sulfate, filtered, andevaporated to dryness. The resulting crude compound was purified bycolumn chromatography eluting with 20 to 80% ethyl acetate/hexanes toyield the 3′H-spiro[1,3]dioxolane-1-{2-[2-(hydroxy)-ethyl]-allyl}-1-hydroxy-10-(4-methoxy-phenyl)-12a-methyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-onecompound as a crystalline yellow solid.

Step 3

3′H-spiro [1,3]dioxolane-1-{2-[2-(hydroxy)-ethyl]-allyl}-1-hydroxy-10-(4-methoxy-phenyl)-12a-methyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-oneether prepared as in Step 2 above (20 mg) was dissolved in acetone (5mL) was prepared and cooled to 0° C. TsOH (0.001 g) was added and theresulting mixture stirred at room temperature for 5 hours. An aqueoussolution of NaHCO₃ was added (100 mL) and EtOAc (100 mL) was added andthe layers were separated. The aqueous layer was extracted with EtOAc(50 mL). The organic layers were washed with water, brine, dried overmagnesium sulfate, filtered, and evaporated to dryness. The resultingcrude compound was purified by column chromatography eluting with 20 to80% ethyl acetate/hexanes to yield the title compound as a crystallineyellow solid.

MS=479.2 (M+H⁺)

EXAMPLE 34 12a-Methyl-10-(4-methylsulfanyl-phenyl)2,3,3a,3b,4,5,9,10,12,12a-decahydro-8H-11-oxa-naphtho[2,1-e]azulene-1,7-dione(Compound #25)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 10.

MS=409.2

EXAMPLE 351-Acryloyl-1-hydroxy-12a-methyl-10-(4-methylsulfanyl-phenyl)2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one

Step 1

A solution of 1-methoxyallene (0.3 ml, 1 mmol) in THF (5 mL) wasprepared and cooled to −78° C. and then n-BuLi (3.5 mL, 1.6 M solutionin hexanes) was added and the resulting mixture stirred at −78° C. for 3min. To the reaction mixture was then added a solution of3′H-spiro[[1,3]dioxolane-10-(4-4-methylsulfanyl-phenyl)-12a-methyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-8H-11-oxa-naphtho[2,1-e]azulene-1,7-dione(120 mg in 5 ml of THF) prepared as in Example 10 above, and theresulting mixture stirred for 30 min. An aqueous solution of NaHCO₃ wasadded (300 mL) and EtOAc (300 mL) was added and the layers wereseparated. The aqueous layer was extracted with EtOAc (350 mL). Theorganic layers were washed with water, brine, dried over magnesiumsulfate, filtered, and evaporated to dryness. The resulting crudecompound was purified by column chromatography eluting with 20 to 80%ethyl acetate/hexanes to yield3′H-spiro[1,3]dioxolane1-Hydroxy-1-(1-methoxy-propa-1,2-dienyl)-12a-methyl-10-(4-methylsulfanyl-phenyl)-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one.

Step 2

The title compound was prepared as a white solid according to theprocedure described in Example 7, starting from the compound prepared ina step 1 above.

MS=464.2

EXAMPLE 3610-(4-Methoxy-phenyl)-12a-methyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-8H-11-oxa-naphtho[2,1-e]azulene-1,7-dione(Compound #28)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 11.

MS=393.2

¹H NMR (400 MHz, CDCl₃): δ 7.22 (2H, d, J=8.8 Hz), 6.89 (2H, d, J=8.8Hz), 5.80 (1H, s), 5.36 (1H, s), 3.75 [center of AB quartet,J_(AB)=12.1, Δν=299 Hz, δ_(A)=4.13, δ_(B)=3.38, 2H], 3.80 (3H, s),2.92-1.56 (14H, m), 1.18 (3H, s).

EXAMPLE 3710-α-(4-Methoxy-phenyl)-12a-methyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-8H-11-oxa-naphtho[2,1-e]azulene-1,7-dione(Compound #29)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 11.

MS=393.2

EXAMPLE 381-Hydroxy-1-isopropenyl-10-(4-methanesulfonyl-phenyl)-12a-methyl-2,3,3a,3b,4,5,9,10,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #30)

1-Hydroxy-1-isopropenyl-12a-methyl-10-(4-methylsulfanyl-phenyl)-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one,prepared as in Example 12 above, (10 mg) dissolved in ethyl acetate (5mL) was prepared and cooled to 0° C. Oxone® (100 mg) was added and theresulting mixture stirred at room temperature for 1 hours. An aqueoussolution of NaHCO₃ was added (100 mL) and EtOAc (100 mL) was added andthe layers were separated. The aqueous layer was extracted with EtOAc(50 mL). The organic layers were washed with water, brine, dried overmagnesium sulfate, filtered, and evaporated to dryness. The resultingcrude compound was purified by column chromatography eluting with 20 to80% ethyl acetate/hexanes to yield the title compound as a crystallineyellow solid.

MS=484.2 (M+H⁺)

EXAMPLE 39 10-(4-Dimethylamino-phenyl)-1-hydroxy-12a-methyl-1-phenylethynyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #31)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 6.

MS=507.28

EXAMPLE 4010-(4-Dimethylamino-phenyl)-1-(2-fluoro-phenylethynyl)-1-hydroxy-12a-methyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #32)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 6.

MS=527.3.28, LC-MS 525 (M⁺)

¹H NMR (400 MHz, CDCl₃): δ 7.38-7.26 (2H, m), 7.20 (2H, d, J=8.7 Hz),7.12-6.99 (2H, m), 6.98 (2H, d, J=5.34), 5.76 (1H, s), 5.58 (s, 1H),[center of AB quartet, J_(AB)=11.7, Δν=83 Hz, δ_(A)=3.98, δ_(B)=3.77,2H], 2.94 (6H, s), 2.88-2.68 (m, 3H), 2.51-2.27 (m, 6H), 2.19-2.11 (m,1H), 1.97 (OH, s), 1.85-1.61 (m, 4H), 1.21 (3H, s).

EXAMPLE 4110-(4-Dimethylamino-phenyl)-1-(3-fluoro-phenylethynyl)-1-hydroxy-12a-methyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one (Compound #34)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 6.

MS=527.3.28

EXAMPLE 4210-(4-Dimethylamino-phenyl)-1-(4-fluoro-phenylethynyl)-1-hydroxy-12a-methyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #35)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 6.

MS=527.3.28

EXAMPLE 431-(3,5-Difluoro-phenylethynyl)-10-(4-dimethylamino-phenyl)-1-hydroxy-12a-methyl-2,3,3a,3b,4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound # 36)

The title compound was prepared as a white solid according to theprocedure described in Example 7 starting from the compound prepared asin Example 6.

MS=544.3.21

EXAMPLE 44 10-(4-Dimethylamino-phenyl)-1-hydroxy-12a-methyl-1-pentafluoroethyl2,3,3a,3b4,5,9,10,12,12a-decahydro-1H,8H-11-oxa-naphtho[2,1-e]azulen-7-one(Compound #37)

The title compound was prepared as a white solid according to theprocedure described in Example 15 starting from the compound prepared asin Example 6.

MS=526.13

¹H NMR (400 MHz, CDCl₃): δ 7.15 (2H, d, J=8.8 Hz), 6.67 (2H, d, J=8.8Hz), 5.76 (1H, s), 5.77 (1H, s), 5.48 (1H, s), 4.09-4.03 (1H, m),3.68-3.61 (1H, m), 2.94 (6H, s), 2.91-2.86 (1H, m), 2.72-2.58 (2H, m),2.58-2.37 (4H, m), 2.34-2.20 (2H, m), 1.96-1.77 (3H, m), 1.76-1.68 (2H,m), 1.26 (3H, s).

EXAMPLE 45 T47D Human Breast Cancer Cells Assay

T47D human breast cancer cells were grown in RPMI medium without phenolred (Invitrogen) containing 10% (v/v) heat-inactivated fetal bovineserum (FBS; Hyclone), 1% (v/v) penicillin-streptomycin (Invitrogen), 1%(w/v) glutamine (Invitrogen), and 10 mg/mL insulin (Sigma). Incubationconditions were 37° C. in a humidified 5% (v/v) carbon dioxideenvironment.

The cells were plated in 96-well tissue culture plates at 10,000 cellsper well in assay medium [RPMI medium without phenol red (Invitrogen)containing 5% (v/v) charcoal-treated FBS (Hyclone) and 1% (v/v)penicillin-streptomycin (Invitrogen)]. Two days later, the medium wasdecanted and test compound or control were added at a finalconcentration of 0.1% (v/v) dimethyl sulfoxide in fresh assay medium.Twenty-four hours later, an alkaline phosphatase assay was performedusing a SEAP kit (BD Biosciences Clontech, Palo Alto, Calif.). Briefly,the medium was decanted and the cells were fixed for 30 minutes at roomtemperature with 5% (v/v) formalin (Sigma). The cells were washed oncewith room temperature Hank's buffered saline solution (Invitrogen).Equal volumes (0.05 mL) of 1× Dilution Buffer, Assay Buffer and 1:20substrate/enhancer mixture were then added. After 1 hour incubation atroom temperature in the dark, the lysate was transferred to a white96-well plate (Dynex) and luminescence was read using a LuminoSkanAscent (Thermo Electron, Woburn, Mass.).

EXAMPLE 46 A549Human Lung Cell Assay

A549Human lung carcinoma cells were grown in F-12K Nutrient Mixturecontaining 10% (v/v) fetal bovine serum (FBS; Invitrogen), 2 mMglutamine and 0.15% sodium dicarbonate (Invitrogen).

A549 cells were split 1 to 3 in 175 cm tissue culture flask. The cellswere incubated at 37° C. in CO₂ incubator until the cells were 95%confluent (typically 24-30 hours).

The following solutions were prepared in sterile tubes: (a) Solution A1.5 μg/ml of DNA in 8.5 ml OPTI-MEM I Reduced Serum Medium. (GIBCO cat#31985) and (b) Solution B: 6 μl/ml of DMRIE-C Reagent into 8.5 μlOPTI-MEM I. The two solutions were combined and mixed gently, thenincubated at room temperature for 40 minutes.

The A549 cells prepared above were washed with 100 μl of OPTI-MEM I. Themedium was removed and 17 ml of the lipid-DNA complex solution wasoverlayed onto cells. The cells ere then incubated for 16 h at 37° C. inCO₂ incubator. The DNA-containing medium was removed and 30 ml of growthmedium was added. (5% Charcoal treated FBS) After 5-6 h, the cells wereseeded in a 96 well plate and the cells incubated overnight at 37° C. inCO₂ incubator.

To each well was then added 5 μl of test compounds and the cellsincubated at 37° C. for 10 min. 5 μL of dexamathasone (CAS [50-02-2]),was then added to each well for challenger and the cells incubated at37° C. in CO₂ incubator for 24 h. 100 μl of Luc-assay buffer was thenadded into each cell well and the cells incubated for 30 min at roomtemperature. A 150 μL sample from each well was then transferred into aDYNEX Microlitel plate and read on Top-counter.

Representative compounds of the present invention were tested accordingto the procedures described in Examples 45 and 46 above, with results aslisted in Table 2 below.

TABLE 2 Biological Results A 549 T47D Compound No. IC₅₀ (nM) IC₅₀ (nM) 150.07 0.4 2 58.19 5.12 3 132.92 7 4 68.71 33.25 5 7.06 54 6 108.98 83 716.17 115.7 9 625.72 264 10 >3000 1800 11 >3000 >1000 12 117.92 >1000 13367.04 >1000 14 46 >1000 15 583.43 >1000 16 >3000 >1000 17 114.17 >100018 >3000 >1000 19 >3000 >1000 20 >3000 >1000 21 >1000 >100022 >3000 >1000 23 237.46 260 24 771.03 176, 130 25 1317.4 26 2313.96 2741.52 28 >3000 29 >3000 30 >1000 31 78 32 48 34 122 35 17 36 160 37 4238 1.1

EXAMPLE 47

As a specific embodiment of an oral composition, 100 mg of the compound#5 is formulated with sufficient finely divided lactose to provide atotal amount of 580 to 590 mg to fill a size O hard gel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A compound of formula (I)

R¹ is selected from the group consisting of —NR^(A)R^(B), —O—R^(A),—S—R^(A) and —SO₂—R^(A); wherein R^(A) and R^(B) are each independentlyselected from the group consisting of hydrogen and C₁₋₄alkyl; R² isselected from the group consisting of C₁₋₄alkyl, —C₁₋₄alkyl-OH,halogenated C₁₋₄alkyl, C₂₋₄alkenyl, —C₂₋₄alkenyl-OH, —C₂₋₄alkenyl-CF₃,C₂₋₄alkynyl, —C₂₋₄alkynyl-CF₃, —C₂₋₄alkynyl-phenyl, —C(O)—C₂₋₄alkyl,—C(O)—C₂₋₄alkenyl and —C(O)-phenyl; wherein the phenyl, whether alone oras part of a substituent group, is optionally substituted with one totwo substituents independently selected from the group consisting ofhalogen, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinatedC₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino and di(C₁₋₄alkyl)amino;R³is —OH; alternatively, R² and R³ are taken together with the carbonatom to which they are bound to form C(O) or2-(3-methylene-tetrahydro-furanyl); or a pharmaceutically acceptablesalt or ester thereof.
 2. A compound as in claim 1, wherein R¹ isselected from the group consisting of NR^(A)R^(B), —OR^(A), —SR^(A) and—SO₂—R^(A); wherein R^(A) and R^(B) are each independently selected fromthe group consisting of hydrogen and C₁₋₂alkyl; R² is selected from thegroup consisting of C₁₋₄alkyl, fluorinated C₁₋₄alkyl, —C₁₋₄alkyl-OH,C₂₋₄alkenyl, —C₂₋₄alkenyl-OH, —C₂₋₄alkenyl-CF₃, C₂₋₄alkynyl,—C₂₋₄alkynyl-CF₃, —C₂₋₄alkynyl-phenyl, —C(O)—C₂₋₄alkyl, and—C(O)—C₂₋₄alkenyl; wherein the phenyl is optionally substituted with oneto two substituents independently selected from the group consisting ofhalogen, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy and fluorinatedC₁₋₄alkoxy; R³ is —OH; alternatively, R² and R³ are taken together withthe carbon atom to which they are bound to form C(O) or2-(3-methylene-tetrahydro-furanyl); or a pharmaceutically acceptablesalt or ester thereof.
 3. A compound as in claim 2, wherein R¹ isselected from the group consisting of NR^(A)R^(B), —OR^(A), —SR^(A) and—SO₂—R^(A); wherein R^(A) and R^(B) are each independently selected fromC₁₋₂alkyl; R² is selected from the group consisting of fluorinatedC₁₋₃alkyl, C₂₋₄alkenyl, —C₂₋₄alkenyl-OH, C₂₋₄alkynyl; —C₂₋₄alkynyl-CF₃,—C₂₋₄alkynyl-phenyl, and —C(O)—C₂₋₄alkenyl; wherein the phenyl isoptionally substituted with one to two substituents independentlyselected from the group consisting of halogen, C₁₋₄alkyl and fluorinatedC₁₋₃alkyl; R³ is —OH; alternatively, R² and R³ are taken together withthe carbon atom to which they are bound to form C(O) or2-(3-methylene-tetrahydro-furanyl); or a pharmaceutically acceptablesalt or ester thereof.
 4. A compound as in claim 3, wherein R¹ isselected from the group consisting of dimethylamino, methoxy, methylthioand methylsulfonyl; R² is selected from the group consisting of—CF₂—CF₃, —CH(═CH₂)—CH₃, —CH₂—CH═CH₂, —CCH, —CC—CH₃, —CC—CF₃,—CC-phenyl, —CC-(4-trifluoromethyl-phenyl), —CC-(4-t-butyl-phenyl),—CC-(2-fluor-phenyl), —CC-(3-fluoro-phenyl), —CC-(4-fluoro-phenyl),—CC-(3,5-difluoro-phenyl), —CH(═CH₂)—CH₂—CH₂—OH and —C(O)—CH═CH₂; R³ is—OH; alternatively, R² and R³ are taken together with the carbon atom towhich they are bound to form C(O) or 2-(3-methylene-tetrahydro-furanyl);or a pharmaceutically acceptable salt or ester thereof.
 5. A compound asin claim 4, wherein R¹ is selected from the group consisting ofdimethylamino, methoxy and methylthio; R² is selected from the groupconsisting of —CF₂—CF₃, —CH(═CH₂)—CH₃, —CCH and —CC—CH₃; R³ is —OH; or apharmaceutically acceptable salt or ester thereof.
 6. A compound as inclaim 4, wherein R¹ is selected from the group consisting ofdimethylamino, methoxy and methylthio; R² is selected from the groupconsisting of —CF₂—CF₃, —CH(═CH₂)—CH₃, —CCH, —CC-phenyl,—CC-(2-fluoro-phenyl), —CC-(4-fluoro-phenyl) and—CC-(4-trifluoromethyl-phenyl); R³is —OH; alternatively, R² and R³ aretaken together with the carbon atom to which they are bound to form2-(3-methylene-tetrahydro-furanyl); or a pharmaceutically acceptablesalt or ester thereof.
 7. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of claim
 1. 8. Acompound of formula (II)

R¹ is selected from the group consisting of —NR^(A)R^(B), —O—R^(A),—S—R^(A) and —SO₂—R^(A); wherein R^(A) and R^(B) are each independentlyselected from the group consisting of hydrogen and C₁₋₄alkyl; R² isselected from the group consisting of C₁₋₄alkyl, —C₁₋₄alkyl-OH,halogenated C₁₋₄alkyl, C₂₋₄alkenyl, —C₂₋₄alkenyl-OH, —C₂₋₄alkenyl-CF₃,C₂₋₄alkynyl, —C₂₋₄alkynyl-CF₃, —C₂₋₄alkynyl-phenyl, —C(O)—C₂₋₄alkyl,—C(O)—C₂₋₄alkenyl and —C(O)-phenyl; wherein the phenyl, whether alone oras part of a substituent group, is optionally substituted with one totwo substituents independently selected from the group consisting ofhalogen, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinatedC₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino and di(C₁₋₄alkyl)amino;or a pharmaceutically acceptable salt or ester thereof.
 9. A compound asin claim 8, wherein R¹ is selected from the group consisting of —SR^(A)and —SO₂—R^(A); wherein R^(A) and R^(B) are each independently selectedfrom the group consisting of hydrogen and C₁₋₂alkyl; R² is selected fromthe group consisting of C₁₋₄alkyl, fluorinated C₁₋₄alkyl, —C₁₋₄alkyl-OH,C₂₋₄alkenyl, —C₂₋₄alkenyl-OH, —C₂₋₄alkenyl-CF₃, C₂₋₄alkynyl,—C₂₋₄alkynyl-CF₃, —C₂₋₄alkynyl-phenyl, —C(O)—C₂₋₄alkyl, and—C(O)—C₂₋₄alkenyl; wherein the phenyl is optionally substituted with oneto two substituents independently selected from the group consisting ofhalogen, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy and fluorinatedC₁₋₄alkoxy; or a pharmaceutically acceptable salt or ester thereof. 10.A compound as in claim 9, wherein R¹ is selected from the groupconsisting of —SR^(A); wherein R^(A) is selected from C₁₋₃alkyl; R² isselected from the group consisting of —CC-phenyl; wherein the phenyl isoptionally substituted with one to two substituents independentlyselected from the group consisting of halogen, C₁₋₄alkyl and fluorinatedC₁₋₃alkyl; or a pharmaceutically acceptable salt or ester thereof.
 11. Acompound as in claim 10, selected from the group consisting of thecompound of formula (IIa)

and pharmaceutically acceptable salts or esters thereof.